JP2011506487A - Translocator protein ligand - Google Patents

Abstract

  The present invention relates to compounds and methods for imaging translocator protein (18 kDa) (TSPO) expression in a subject. The invention also relates to compounds and methods for the treatment of neurodegenerative disorders, inflammation or anxiety in a subject.

Description

  The present invention relates to compounds and methods for imaging translocator protein (18 kDa) (TSPO) expression in a subject. The invention also relates to compounds and methods for the treatment of neurodegenerative disorders, inflammation or anxiety in a subject, and is described herein below with reference to this application. However, it will be appreciated that the invention is not limited to this particular field of application.

  Throughout this specification, any discussion of the prior art should in no way be considered an admission that such prior art is widely known in the art or forms part of the common general knowledge.

  Translocator protein (18 kDa) (TSPO), formerly known as peripheral benzodiazepine receptor (PBR), is trimeric with adenine nucleotide carrier (ANC) (30 kDa) and voltage-dependent anion channel (VDAC) (32 kDa) Somatic complexes can be formed and mitochondrial permeability transition pores (MPTP) can be constructed. TSPO is distinguished from central benzodiazepine receptor (CBR) by its distinct structure, physiological function and intracellular location on the mitochondrial outer membrane. Although TSPO has been implicated in numerous biological processes, other aspects of its physiological role have not yet been clarified. Studies indicate that TSPO is involved in the rate-limiting step of steroid biosynthesis, immune modification, porphyrin transport, calcium homeostasis and programmed cell death.

  TSPO is glioblastoma (Non-patent document 1, Non-patent document 2, Non-patent document 3), Multiple sclerosis (Non-patent document 4, Non-patent document 5, Non-patent document 6, Non-patent document 7, Non-patent document 7, Patent Document 8), Ischemic Stroke (Non-Patent Document 9, Non-Patent Document 10, Non-Patent Document 11), Herpes Encephalitis (Non-Patent Document 12), Parkinson's Disease (Non-Patent Document 13, Non-Patent Document 14, Non-Patent Document) 15, non-patent document 16, non-patent document 17), HIV (non-patent document 18, non-patent document 19, non-patent document 20), amyotrophic lateral sclerosis (non-patent document 21), cortical basal ganglia degeneration (Non-patent document 22, Non-patent document 23), Huntington's chorea (Non-patent document 24), Cancer (Non-patent document 25, Non-patent document 26, Non-patent document 27), Alzheimer's disease (Non-patent document 28, Non-patent document; Patent document 29), depression (non-patent document 30, non-patent document) Reference 31), and cancer, it is to be involved in various diseases including autoimmune diseases, infectious diseases and neurodegenerative diseases (Non-Patent Document 32). It is widely accepted that ligands for TSPO may be effective in the treatment of such diseases.

  TSPO is densely distributed in most peripheral organs, including lung, heart and kidney, but is minimally expressed in normal brain parenchyma. After neuronal injury or infection, TSPO expression in the brain parenchyma increases dramatically. In vitro autoradiography and immunohistochemistry showed that increased TSPO binding in this region was directly correlated with the appearance of activated microglia. Recently, in vivo positron emission tomography (PET) imaging in patients with Alzheimer's disease (AD) and multiple sclerosis (MS) has limited TSPO binding in brain parenchyma to activated microglial cells. Was confirmed.

  Microglia are the main immune effector cells of the central nervous system (CNS). These macrophage-like immune cells are thought to be derived from the monocyte lineage and their main role is in host defense and immune surveillance. They are highly sensitive to changes in their microenvironment and quickly become activated in response to pathological events. For this reason, TSPO is thought to be first associated with early inflammatory processes in the early stages of several neurodegenerative disorders.

  TSPO including benzodiazepine (diazepam and Ro5-4864), isoquinolinecarboxamide (PK11195), indoleacetamide (FGIN-1-27), phenoxyphenyl-acetamide (DAA1106), pyrazolopyrimido (DPA-713), benzothiazepine and imidazopyridine Several classes of ligands have been reported over the past decades. Several other classes have also been developed. However, to better characterize the physiological and therapeutic roles of TSPO, its precise localization and the expected presence of TSPO subtypes, it has more binding properties and biological activities, A wide range of ligands is required.

Isoquinolinecarboxamide [ ¹¹ C] (R) -PK11195 has been used as a pharmacological probe to study TSPO function and expression. Several PET studies conducted in patients with AD, MS, and multiple system atrophy (MSA) enable in vivo measurement of TSPO in the living brain using [ ¹¹ C] (R) -PK11195 It was shown to be possible. [ ¹¹ C] (R) -PK11195 is considered the most widely used PET TSPO ligand, but shows only a poor signal-to-noise ratio and low brain permeability, which ultimately leads to It has decreased its sensitivity as a marker of microglial activation.

In 1998, phenoxyphenyl-acetamide derivative DAA1106 was reported as a highly selective and potent ligand of TSPO (Non-patent Document 33). DAA1106 was labeled with carbon-11 ( ¹¹ C) and was used in PET studies to assess its in vivo kinetics in both rodent and primate brains (34). Reference 3). Binding of ^[11 C] DAA1106 are found to ^[11 C] (R) 4 times more than -PK11195 in monkey occipital cortex, indicating its superior brain permeability. A fluorine-18 ( ¹⁸ F) analog of this compound, ie, [ ¹⁸ F] FEDAA1106, was also synthesized, and this analog also exhibits binding properties similar to [ ¹¹ C] DAA1106 in vivo (Non-patent Document 36). ). However, the binding of both [ ¹¹ C] DAA1106 and [ ¹⁸ F] FEDAA1106 appears to be irreversible, and in fact its slow elimination from the brain indicates that they have suitable kinetics for quantitative analysis. Indicates that it may not have.

  Non-Patent Document 37 reports that TSPO ligand PK11195 reduces microglia activation and neuronal cell death in the rat layer injected with quinolinic acid. The results reported in this paper show that the inflammatory response from activated microglia adversely affects striatal neurons, and therefore pharmacological targeting of TSPO in microglia is likely to protect neurons in neurological diseases I suggest that.

  More recently, in Patent Document 1, the applicants described that DPA that specifically binds with high affinity to 2-arylpyrazolo (1,5-α) pyrimidin-3-ylacetamide derivatives, particularly TSPO, as a ligand. -714.

  Patent Document 2 discloses a fluorinated ligand for targeting a peripheral benzodiazepine receptor.

  The identification of TSPO ligands with improved brain dynamics that can be used to image TSPO expression in vivo is such that such ligands are involved in the first stages of several neurodegenerative disorders. It may be advantageous that it could be used to further investigate the cascade of events. Also, identifying TSPO ligands with improved brain dynamics is advantageous because such ligands have the potential to serve as diagnostic and therapeutic tools for neurodegenerative disorders.

WO2007 / 134362 International application WO2008 / 022396

Pappata et al., 1991 J Nucl Med 32: 1608-10. Veenman et al., 2004 Biochem Pharmacol. 68 (4): 689-98 Levin, 2005 Biochemistry 44 (29): 9924-35. Vowinckel et al., 1997 J Neurosci Res 50: 345-53. Banati et al., 2000 Brain 123 (Pt 11): 2321-37. Debryne et al., 2003 Eur J Neurol 10: 257-64. Versijpt et al., 2005 Multi Scroller 11: 127-34 Chen and Guilarte, 2006 Toxicol Sci. 91 (2): 532-9 Gerhard et al., 2000 Neuroport; 11: 2957-60 Gerhard et al., 2005 Neuroimage 24: 591-5. Price et al., 2006 Stroke 37: 1749-53. Cagnan et al., 2001 Brain; 124: 2014-27 Cumming et al., 2001. Acta Neurol Scan 103: 309-15 Cicetti et al., 2002 Eur J Neurosci 15: 991-8 Ouchi et al., 2005 57: 168-75. Gerhard et al., 2006 Neurobiol Dis 21: 404-12. Cumming et al., 2006 Synapse 59: 418-26 Vennetti et al., 2004 J Clin Invest 113: 981-9. Hammaud et al., 2005 J Neurovirol 11: 346-55. Wiley et al., 2006 J Neurovirol 12: 262-71. Turner et al., 2004 Neurobiol Dis 15: 601-9. Henkel et al., 2004 Mov Disod 19: 817-21 Gerhard et al., 2004 Mov Disod 19: 1221-6 Pavese et al., 2006 Neurology 66: 1638-43. Hardwick et al., 2002 Cancer Genet Cytogene. 139 (1): 48-51 Papadopoulo V. 2003 Ann Pharm Fr. 61 (1): 30-50 Han Z. 2003 J Receive Signal Trans Res. 23 (2-3): 225-38 Papadopoulo V. 2003 Ann Pharm Fr. 61 (1): 30-50 Li et al., 2007 Biochem Pharmaco. 73 (4): 491-503 Gavioli EC. 2003 Eur J Pharmacol. 13; 471 (1): 21-6 Kita A.I. 2004 Br J Pharmacol. 142 (7): 1059-72 Galiegue et al., 2003 Curr Med Chem 10: 1563-72. Chaki, S .; Funakoshi, T .; Yoshikawa, R .; Okuyama, S .; Okbo, T .; Nakazato, A .; Nagamine, M .; Tomisawa, K .; European Journal of Pharmacology, 1999, 371, 197-204. Zhang MR, Kida T, Noguchi J et al. [11C] DAA 1106: radiosynthesis and in vivo binding to peripheral benzoreceptors in mouse brain. Nucl Med Biol 2003; 30: 513-519 Maeda J, Suhara T, Zhang MR, et al. Novel peripheral benzodiapine receptor receptor [11C] DAA1106 for PET: Animating tools for the incells in the cells. Synapse. 2004; 52: 283-291 Zhang MR, Maeda J, Ogawa M, et al. Development of a new radical, N- (5-fluoro-2-phenephenylphenyl) -N- (2- [18F] fluoroethylenemethylenepetoxymethylenebenzoylphenyl in prime brain. J Med Chem. 2004; 47: 2228-2235 Ryu JK et al., Neurobiology of Disease, 20 (2005) 550-561.

  One object of the present invention is to overcome or ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative.

  In its preferred form, an object of the present invention is to provide compounds and methods for imaging translocator protein (18 kDa) (TSPO) expression in a subject. In its preferred form, the object of the present invention is also to provide compounds and methods for the treatment of neurodegenerative disorders, inflammation or anxiety in a subject.

［式中、
Ｒ^１２およびＲ^１３は、各々独立に、Ｈ、ベンジル、Ｃ_１−Ｃ_１０アルキル、Ｃ_２−Ｃ_１０アルケニル、Ｃ_２−Ｃ_１０アルキニル、アリールおよびヘテロアリールからなる群から選択され、これらは各々、１以上のハロまたはＣ_１−Ｃ_６アルキルで置換されていてもよく；
またはＲ^１２およびＲ^１３は、それらが結合する窒素と共に、置換されていてもよい、３ないし７環員を有する複素環を形成し；
Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７およびＲ^１８は、各々独立に、Ｈ、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいＮＨＣ_１−６アルキル、置換されていてもよいＳＣ_１−６アルキル、ＣＯＯＲ^２２、（ＣＨ_２）_ｎＯＲ^２２または置換されていてもよいポリエーテルであり；
Ｒ^１９およびＲ^２１は、各々独立に、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいＮＨＣ_１−６アルキル、置換されていてもよいＳＣ_１−６アルキル、ＣＯＯＲ^２２、（ＣＨ_２）_ｎＯＲ^２２または置換されていてもよいポリエーテルであり；
Ｒ^２０は、Ｈ、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいＮＨＣ_１−６アルキル、置換されていてもよいＳＣ_１−６アルキル、ＣＯＯＲ^２２、（ＣＨ_２）_ｎＯＲ^２２または置換されていてもよいポリエーテルであり；
Ｒ^２２は、置換されていてもよいアルキルであり；
ｎは、１から６の整数である］
で示される化合物またはその塩または溶媒和物を提供する。 According to a first aspect, the present invention provides a compound of formula (III)

[Where:
R ¹² and R ¹³ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ¹² and R ¹³ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 7 ring members that may be substituted;
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ²² , (CH ₂ ) _n OR ²² or an optionally substituted polyether;
R ¹⁹ and R ²¹ are each independently halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, Aryl which may be substituted, heteroaryl which may be substituted, NHC _1-6 alkyl which may be substituted, SC _1-6 alkyl which may be substituted, COOR ²² , (CH ₂ ) _n OR ²² or an optionally substituted polyether;
R ²⁰ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ²² , (CH ₂ ) _n OR ²² or substituted Which may be a polyether;
R ²² is an optionally substituted alkyl;
n is an integer from 1 to 6]
Or a salt or solvate thereof.

R ²⁰ is preferably H.

R ¹⁹ and R ²¹ are preferably each independently C _1-6 alkyl. More preferably, R ¹⁹ and R ²¹ are each independently methyl.

R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H, halo, OH, NO ₂ , optionally substituted C _1-6 alkyl, optionally substituted OC _1- It is preferably ₆ alkyl or optionally substituted aryl. R ¹⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ are more preferably H.

Even more preferably, R ¹⁶ is halo, OH, optionally substituted C _1-6 alkyl or optionally substituted OC _1-6 alkyl.

R ¹² and R ¹³ are preferably each independently C _1-6 alkyl. More preferably, R ¹² and R ¹³ are each independently ethyl.

R ¹⁶ is preferably OCH ₃ , CH ₃ , Cl, Br, F, OH, OCH ₂ CH ₂ OTs or OCH ₂ CH ₂ F.

In certain embodiments, R ¹² and R ¹³ are each independently from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl. Selected, each of which may be substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ¹² and R ¹³ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 7 ring members that may be substituted;
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ²² , (CH ₂ ) _n OR ²² or an optionally substituted polyether;
R ¹⁹ and R ²¹ are each independently halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, Aryl which may be substituted, heteroaryl which may be substituted, NHC _1-6 alkyl which may be substituted, SC _1-6 alkyl which may be substituted, COOR ²² , (CH ₂ ) _n OR ²² or an optionally substituted polyether;
R ²⁰ is H;
R ²² is an optionally substituted alkyl;
n is preferably an integer of 1 to 6.

R ¹² and R ¹³ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ¹² and R ¹³ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 7 ring members that may be substituted;
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ²² , (CH ₂ ) _n OR ²² or an optionally substituted polyether;
R ¹⁹ and R ²¹ are each independently C _1-6 alkyl;
R ²⁰ is H;
R ²² is an optionally substituted alkyl;
n is preferably an integer of 1 to 6.

R ¹² and R ¹³ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ¹² and R ¹³ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 7 ring members that may be substituted;
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ²² , (CH ₂ ) _n OR ²² or an optionally substituted polyether;
R ¹⁹ and R ²¹ are each independently methyl;
R ²⁰ is H;
R ²² is an optionally substituted alkyl;
n is preferably an integer of 1 to 6.

R ¹² and R ¹³ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ¹² and R ¹³ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 7 ring members that may be substituted;
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H, halo, OH, NO ₂ , optionally substituted C _1-6 alkyl, optionally substituted OC _{1- 6} alkyl or optionally substituted aryl;
R ¹⁹ and R ²¹ are each independently methyl;
R ²⁰ is preferably H.

Preferably, R ¹² and R ¹³ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, Each of which may be substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ¹² and R ¹³ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 7 ring members that may be substituted;
R ¹⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ are H;
R ¹⁶ is, H, halo, OH, NO _2, be a substituted _{C 1-6} alkyl optionally, optionally substituted _{OC 1-6} alkyl or optionally substituted aryl;
R ¹⁹ and R ²¹ are each independently methyl;
R ²⁰ is preferably H.

R ¹² and R ¹³ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ¹² and R ¹³ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 7 ring members that may be substituted;
R ¹⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ are H;
R ¹⁶ is halo, OH, optionally substituted C _1-6 alkyl or optionally substituted OC _1-6 alkyl;
R ¹⁹ and R ²¹ are each independently methyl;
R ²⁰ is preferably H.

R ¹² and R ¹³ are each independently C _1-6 alkyl;
R ¹⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ are H;
R ¹⁶ is halo, OH, optionally substituted C _1-6 alkyl or optionally substituted OC _1-6 alkyl;
R ¹⁹ and R ²¹ are each independently methyl;
R ²⁰ is preferably H.

R ¹² and R ¹³ are each independently ethyl;
R ¹⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ are H;
R ¹⁶ is halo, OH, optionally substituted C _1-6 alkyl or optionally substituted OC _1-6 alkyl;
R ¹⁹ and R ²¹ are each independently methyl;
R ²⁰ is more preferably H.

および

からなる群またはそれらの塩または溶媒和物から選択されることが好ましい。 The compound according to the first aspect is

and

It is preferably selected from the group consisting of or a salt or solvate thereof.

［式中、
Ｒ^２３およびＲ^２４は、各々独立に、Ｈ、ベンジル、Ｃ_１−Ｃ_１０アルキル、Ｃ_２−Ｃ_１０アルケニル、Ｃ_２−Ｃ_１０アルキニル、アリールおよびヘテロアリールからなる群から選択され、これらは各々、１以上のハロまたはＣ_１−Ｃ_６アルキルで置換されていてもよく；
または、Ｒ^２３およびＲ^２４は、それらが結合する窒素と共に、置換されていてもよい、３ないし７環員を有する複素環を形成し；
Ｒ^２５、Ｒ^２６、Ｒ^２７、Ｒ^２８およびＲ^２９は、各々独立に、Ｈ、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいＮＨＣ_１−６アルキル、置換されていてもよいＳＣ_１−６アルキル、ＣＯＯＲ^３０、（ＣＨ_２）_ｎＯＲ^３０または置換されていてもよいポリエーテルであり；
Ｒ^３０は、置換されていてもよいアルキルであり；
ｎは、１から６の整数であり；
Ｘは、Ｏ、ＮＨおよびＳからなる群から選択され；
Ｉ、Ｊ、ＫおよびＬは、各々独立にＣＲ^３１またはＮであり；
Ｒ^３１は、Ｈ、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいＮＨＣ_１−６アルキル、置換されていてもよいＳＣ_１−６アルキル、ＣＯＯＲ^３０、（ＣＨ_２）_ｎＯＲ^３０または置換されていてもよいポリエーテルであり；
Ｒ^３３、Ｒ^３４、Ｒ^３５およびＲ^３６は、各々独立に、Ｈ、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである］
で示される化合物またはその塩または溶媒和物を提供する。 According to a second aspect, the present invention provides a compound of formula (IV)

[Where:
R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or an optionally substituted polyether;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is selected from the group consisting of O, NH and S;
I, J, K and L are each independently CR ³¹ or N;
R ³¹ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted Which may be a polyether;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, Optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl]
Or a salt or solvate thereof.

  X is preferably O.

It is preferable that I is N and J, K, and L are CR ³¹ . I, J, K and L are preferably CR ³¹ . Each R ³¹ is preferably independently H, halo or optionally substituted alkyl.

R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are preferably H. R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are preferably H.

R ²⁷ is preferably halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy or optionally substituted aryl. More preferably, R ²⁷ is OH, CH ₃ , OCH ₃ , NO ₂ , F, Cl or naphthyl. Most preferably, R ²⁷ is F, Cl or OCH ₃ .

R ²³ and R ²⁴ are preferably each independently C _1-6 alkyl. More preferably, R ²³ and R ²⁴ are each independently selected from the group consisting of ethyl, propyl and i-propyl.

  The compound according to the second aspect is preferably the (R) -enantiomer.

In certain embodiments, R ²³ and R ²⁴ are each independently from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl. Selected, each of which may be substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or an optionally substituted polyether;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is O;
I, J, K and L are each independently CR ³¹ or N;
R ³¹ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted Which may be a polyether;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, It is preferably an alkynyl which may be substituted, an aryl which may be substituted or a heteroaryl which may be substituted.

R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or an optionally substituted polyether;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is O;
I is N and J, K, L are CR ³¹ ;
R ³¹ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted Which may be a polyether;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, It is preferably an alkynyl which may be substituted, an aryl which may be substituted or a heteroaryl which may be substituted.

R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or an optionally substituted polyether;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is O;
I, J, K and L are CR ³¹ ;
R ³¹ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted Which may be a polyether;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, It is preferably an alkynyl which may be substituted, an aryl which may be substituted or a heteroaryl which may be substituted.

R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or an optionally substituted polyether;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is O;
I, J, K and L are CR ³¹ or I is N and J, K, L are CR ³¹ ;
R ³¹ is independently H, halo or optionally substituted alkyl;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, It is preferably an alkynyl which may be substituted, an aryl which may be substituted or a heteroaryl which may be substituted.

R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁷ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted A good polyether;
R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are H;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is O;
I, J, K and L are CR ³¹ or I is N and J, K, L are CR ³¹ ;
R ³¹ is independently H, halo or optionally substituted alkyl;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, It is preferably an alkynyl which may be substituted, an aryl which may be substituted or a heteroaryl which may be substituted.

R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁷ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted Which may be a polyether;
R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are H;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is O;
I, J, K and L are CR ³¹ or I is N and J, K, L are CR ³¹ ;
R ³¹ is independently H, halo or optionally substituted alkyl;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are preferably H.

R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁷ is halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl;
R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are H;
X is O;
I, J, K and L are CR ³¹ or I is N and J, K, L are CR ³¹ ;
R ³¹ is independently H, halo or optionally substituted alkyl;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are preferably H.

R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁷ is OH, CH ₃ , OCH ₃ , NO ₂ , F, Cl or naphthyl;
R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are H;
X is O;
I, J, K and L are CR ³¹ ; I is N; J, K, L is CR ³¹ ;
R ³¹ is independently H, halo or optionally substituted alkyl;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are preferably H.

R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁷ is F, Cl or OCH ₃ ;
R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are H;
X is O;
I, J, K and L are CR ³¹ or I is N and J, K, L are CR ³¹ ;
R ³¹ is independently H, halo or optionally substituted alkyl;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are preferably H.

R ²³ and R ²⁴ are each independently C _1-6 alkyl;
R ²⁷ is F, Cl or OCH ₃ ;
R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are H;
X is O;
I, J, K and L are CR ³¹ or I is N and J, K, L are CR ³¹ ;
R ³¹ is independently H, halo or optionally substituted alkyl;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are preferably H.

R ²³ and R ²⁴ are each independently selected from the group consisting of ethyl, propyl and i-propyl;
R ²⁷ is F, Cl or OCH ₃ ;
R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are H;
X is O;
I, J, K and L are CR ³¹ or I is N and J, K, L are CR ³¹ ;
R ³¹ is independently H, halo or optionally substituted alkyl;
More preferably, R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are H.

  The compound according to the second aspect is

および

またはその塩または溶媒和物からなる群から選択されることが好ましい。

and

Or it is preferably selected from the group consisting of salts or solvates thereof.

  The compound according to the second aspect is preferably the (R) -enantiomer.

One skilled in the art will appreciate that I, J, K and L are each independently any combination of N or CR ³¹ . It is preferred that I, J, K and L taken together contain 0, 1, 2, 3 or 4 N atoms in any combination. More preferably, I, J, K and L taken together contain 0, 1, 2 or 3 N atoms in any combination. Even more preferably, I, J, K and L taken together comprise any combination of 0, 1 or 2 N atoms. Most preferably, I, J, K and L taken together contain any combination of 0 or 1 N atoms. That is, it is preferable that J is N and I, K, and L are each independently CR ³¹ . Preferably, K is N and I, J and L are each independently CR ³¹ . It is preferred that L is N and I, J and K are each independently CR ³¹ . Most preferably, I is N and J, K and L are each independently CR ³¹ . It is likewise preferred that I, J, K and L are CR ³¹ . Even more preferably, I, J, K and L are CH. I, K and L are CH and J is CR ³¹ where R ³¹ is halo. It is preferred that I, J, K and L together with the two carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring. Preferably the ring may be substituted with halo. More preferably, halo is chloro.

［式中、
Ｒ^２５、Ｒ^２６、Ｒ^２７、Ｒ^２８およびＲ^２９は、各々独立に、Ｈ、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいＮＨＣ_１−６アルキル、置換されていてもよいＳＣ_１−６アルキル、ＣＯＯＲ^３０、（ＣＨ_２）_ｎＯＲ^３０または置換されていてもよいポリエーテルであり；
Ｒ^３０は、置換されていてもよいアルキルであり；
ｎは、１から６の整数であり；
Ｘは、Ｏ、ＮＨおよびＳからなる群から選択され；
Ｉ、Ｊ、ＫおよびＬは、各々独立に、ＣＲ^３１またはＮであり；
Ｒ^３１は、Ｈ、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリール、置換されていてもよいヘテロアリール、置換されていてもよいＮＨＣ_１−６アルキル、置換されていてもよいＳＣ_１−６アルキル、ＣＯＯＲ^３０、（ＣＨ_２）_ｎＯＲ^３０または置換されていてもよいポリエーテルであり；
Ｒ^３３、Ｒ^３４、Ｒ^３５およびＲ^３６は、各々独立に、Ｈ、ハロ、ＯＨ、ＮＯ_２、置換されていてもよいアルキル、置換されていてもよいアルコキシ、置換されていてもよいアルケニル、置換されていてもよいアルキニル、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである］
で示される化合物またはその塩または溶媒和物
（ただし、ＩがＮである場合には、Ｒ^２７はメチルではない）
を提供する。 According to a third aspect, the present invention provides a compound of formula (V) for use as an intermediate in the preparation of a compound of formula (IV)

[Where:
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or an optionally substituted polyether;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is selected from the group consisting of O, NH and S;
I, J, K and L are each independently CR ³¹ or N;
R ³¹ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted Which may be a polyether;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, Optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl]
Or a salt or solvate thereof (provided that when I is N, R ²⁷ is not methyl)
I will provide a.

  X is preferably O.

It is preferable that I is N and J, K, and L are CR ³¹ . It is preferred that I, J, K and L are CR ³¹ . Each R ³¹ is preferably independently H, halo or optionally substituted alkyl.

R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are preferably H. R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are preferably H.

R ²⁷ is preferably halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy or optionally substituted aryl. More preferably, R ²⁷ is OH, CH ₃ , OCH ₃ , NO ₂ , F, Cl or naphthyl. Most preferably, R ²⁷ is F, Cl or OCH ₃ .

  The compound according to the third aspect is preferably the (R) -enantiomer.

  The compound according to the third aspect is

および

からなる群またはその塩または溶媒和物から選択されることが好ましい。

and

Or a salt or solvate thereof.

According to a fourth aspect, the present invention provides a compound according to the first or second aspect radiolabeled with a radioisotope. The radioisotope is preferably selected from ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br. More preferably, the radioisotope is ¹⁸ F.

  According to a fifth aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first, second or fourth aspect or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. To do.

According to a sixth aspect, the invention provides a method of diagnosing a disorder in a subject comprising administering to the subject a compound according to any one of the first, second or fourth aspects. provide. Preferably, the method comprises imaging translocator protein (18 kDa) (TSPO) in the subject.
More preferably, the method includes obtaining an image showing the location of the protein.

Where the compound is radiolabeled with a radioisotope, the radioisotope is preferably selected from the group consisting of ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br. More preferably, the compound is radiolabeled with ¹⁸ F, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br and the image is obtained by positron emission tomography (PET) imaging. Preferably the compound is radiolabeled with ¹²³ I and the image is obtained by SPECT imaging. Preferably, an image is obtained and the degree of TSPO binding of the compound or salt thereof in the subject's brain parenchyma is evaluated.

  The disorder is preferably a neurodegenerative disorder, inflammation or anxiety.

  The disorder is preferably selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumor, anxiety, stress, emotion Disorder or cognitive impairment, glioblastoma, ischemic stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, autoimmune diseases and infectious diseases. The subject is preferably a human.

  According to a seventh aspect, the present invention provides the use of a compound according to the first, second or fourth aspects in the manufacture of a medicament for diagnosing a disorder in a subject.

Diagnosing the disorder preferably includes imaging the translocator protein (18 kDa) in the subject. Where the compound is radiolabeled with a radioisotope, the radioisotope is preferably selected from the group consisting of ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br. Preferably, the compound is radiolabeled with ¹⁸ F, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br and the translocator protein image is obtained by positron emission tomography (PET) imaging. Preferably the compound is radiolabeled with ¹²³ I and a translocator protein image is obtained by SPECT imaging.

  The disorder is preferably a neurodegenerative disorder, inflammation or anxiety.

  Preferably, the disorder is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumor, anxiety, stress, emotion Disorder or cognitive impairment, glioblastoma, ischemic stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, autoimmune diseases and infectious diseases.

［式中、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１５、Ｒ^１６、Ｒ^１７、Ｒ^１８、Ｒ^１９、Ｒ^２０およびＲ^２１は、第１の態様によって定義され、ここで、Ｙは、ＶＩＩと反応する脱離基である。Ｙは、ハロであることが好ましい。 According to an eighth aspect, the present invention provides a method for preparing a compound of formula (III) or a salt or solvate thereof, wherein the method comprises converting a compound of formula (VII) of formula (VIII) Including reacting with compounds

[Wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are defined according to the first aspect, wherein Y is VII Is a leaving group that reacts with. Y is preferably halo.

  According to a ninth aspect, the present invention provides a compound of formula (III) when prepared by the method of the eighth aspect.

［式中、Ｉ、Ｊ、Ｋ、Ｌ、Ｘ、Ｒ^２３、Ｒ^２４、Ｒ^２５、Ｒ^２６、Ｒ^２７、Ｒ^２８、Ｒ^２９、Ｒ^３３、Ｒ^３４、Ｒ^３５およびＲ^３６は、第２の態様によって定義される］。 According to a tenth aspect, the present invention provides a method for preparing a compound of formula (IV) or a salt or solvate thereof, wherein the method comprises converting a compound of formula (V) of formula (VI) Including reacting with compounds

[Wherein, I, J, K, L, X, R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are the second Defined by the embodiment of

  According to an eleventh aspect, the present invention provides a compound of formula (IV) when prepared by the method of the tenth aspect.

  According to a twelfth aspect, the present invention provides a compound according to the first, second or fourth aspect capable of eliciting a response when bound to a TSPO receptor.

  According to a thirteenth aspect, the present invention provides the use of a compound according to the first, second or fourth aspect in the manufacture of a medicament for the treatment of a disorder in a subject. The disorder is preferably characterized by an abnormal density of TSPO receptors in mammals. The disorder is preferably a neurodegenerative disorder, inflammation or anxiety. The disorder is preferably selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumor, anxiety, stress, emotion Disorder or cognitive impairment, glioblastoma, ischemic stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, autoimmune diseases and infectious diseases.

  According to a fourteenth aspect, the present invention provides a method of treating a disorder in a subject comprising administering to the subject a compound according to the first, second or fourth aspect. The disorder is preferably characterized by an abnormal density of TSPO receptors in mammals. The disorder is preferably a neurodegenerative disorder, inflammation or anxiety in the subject.

  The disorder is preferably selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumor, anxiety, stress, emotion Disorder or cognitive impairment, glioblastoma, ischemic stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, autoimmune diseases and infectious diseases.

Rats given [ ¹⁸ F] PDAZ-FE, pre-treated with PK 11195, shown in cross section (top) and partially cut longitudinal section (bottom), aimed in the brain and the ^[18 F] PDAZ-FE is a diagram showing a MicroPET images obtained from the administered rats.

  Preferred embodiments of the invention will now be described, by way of example only, with reference to the accompanying figures.

  Unless the context clearly indicates otherwise, throughout this description and the claims, the terms “comprise”, “comprising” and the like have exclusive or exhaustive meanings. Should be interpreted in an inclusive sense, that is, in the sense of “including but not only”.

As used herein, the term “alkyl” refers to a straight chain, branched or monocyclic or polycyclic alkyl. In general, alkyl _alkyl, with C 1 _{-C 10} alkyl, for example, from 1 to 10 carbon atoms, for example, a nine or ten carbon atoms It is a group. The alkyl group is 1-2, 1-4, 1-6, 1-8, 1-10, 2-4, 2-6, 2-8, 2-10, 4-6, 4-8, 4- It may have 10, 6-8, 6-10 or 8-10 carbon atoms. The alkyl group is preferably C ₁ -C ₆ alkyl.

  Examples of straight and branched alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, s-pentyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl Hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl 1,3-dimethylbutyl, 1,2,2-trimethylpropyl and 1,1,2-trimethylpropyl.

  Examples of cyclic alkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term “alkoxy” refers to a group of formula O alkyl. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy. Generally, the alkoxy _{(alkyoxy), C} 1 _{~C 30} alkoxy, for _example, C 1 _{-C 10} alkoxy, i.e., from 1 to 10 carbon atoms, for example, 1,2,3,4,5,6,7 , Alkoxy groups having 8, 9 or 10 carbon atoms. The alkoxy group is 1-2, 1-4, 1-6, 1-8, 1-10, 2-4, 2-6, 2-8, 2-10, 4-6, 4-8, 4- It may have 10, 6-8, 6-10 or 8-10 carbon atoms. More preferably, the alkoxy is C ₁ -C ₆ alkoxy.

As used herein, the term “alkenyl” refers to straight chain, branched or cyclic alkenyl. Generally, the _alkenyl, C 2 _{-C 10} alkenyl, for example, 2 to 10 carbon atoms, for example, alkenyl groups having 6, 7, 8, 9 or 10 carbon atoms It is. Alkenyl groups have 2 to 4, 2 to 6, 2 to 8, 2 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8, 6 to 10, or 8 to 10 carbon atoms. obtain. Alkenyl group _is preferably a C 2 -C ₆ alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, isobutenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butanedienyl, 1,4-pentadienyl, 1,3- Cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cyclohepta Examples include trienyl and 1,3,5,7-cyclooctatetraenyl.

As used herein, the term “alkynyl” refers to linear, branched or cyclic alkynyl. Generally, _alkynyl, C 2 _{-C 10} alkynyl, for example, 2 to 10 carbon atoms, for example, alkynyl groups having 2,3, 4,5, 6,7, 8,9 or 10 carbon atoms is there. Alkynyl groups have 2 to 4, 2 to 6, 2 to 8, 2 to 10, 4 to 6, 4 to 8, 4 to 10, 6 to 8, 6 to 10, or 8 to 10 carbon atoms. obtain. Alkynyl group _is preferably a C 2 -C ₆ alkynyl.

As used herein, the term “aryl” refers to a single, polynuclear, conjugated or fused aromatic hydrocarbon or aromatic heterocyclic structure radical. Aryl groups are 4-20 carbon atoms, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbons. It preferably has an atom. The aryl group is 4 to 6, 4 to 8, 4 to 10, 4 to 12, 4 to 14, 4 to 16, 4 to 18, 4 to 20, 6 to 8, 6 to 10, 6 to 12, 6 to 14, 6-16, 6-18, 6-20, 8-10, 8-12, 8-14, 8-16, 8-18, 8-20, 10-12, 10-14, 10-16, 10-18, 10-20, 12-14, 12-16, 12-18 12-20, 14-16, 14-18, 14-20, 16-18, 16-20 or 18-20 carbon atoms Can have. Aryl is preferably C ₆ -C ₁₂ aryl. Examples of aryl include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, azulenyl, phenanthryl, pyrenyl and the like. Any available position of the aromatic residue can be used for conjugation with the rest of the molecule of formula (III), (IV) or (V).

  When aryl contains a heterocyclic aromatic ring structure, the heterocyclic structure may contain 1 to 4 heteroatoms independently selected from N, O and S. Aryl containing heteroatoms in the aromatic ring structure is referred to as “heteroaryl”.

  As used herein, the term “heteroaryl” refers to a single, polynuclear, conjugated and fused aromatic group having between 6 and 20 ring atoms, wherein 1 to 3 of these ring atoms. 6, or 1-5 or 1-4 or 1-3 or 1 or 2 are heteroatoms independently selected from the group consisting of N, NH, O and S. Heteroaryl groups are 4-6, 4-8, 4-10, 4-12, 4-14, 4-16, 4-18, 6-10, 6-12, 6-14, 6-16 or 6 It can have ˜18 carbon atoms. A heteroaryl group can have 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 heteroatoms. The heteroatoms can be independently selected from the group consisting of N and NH, N and O, NH and O, N and S, NH and S, and S and O. Examples of such heteroaryl groups include, but are not limited to, pyridyl, thienyl, furyl, pyryl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl , Acridinyl, benzoxazolyl, benzothiazolyl and the like. Any available position of the heteroaromatic residue can be used for conjugation with the remainder of the molecule of formula (III), (IV) or (V). Nitrogen-containing heteroaryl groups can be substituted with an oxygen atom with nitrogen to form an N-oxide. Sulfur-containing heteroaryl groups can be substituted with one or two oxygen atoms with sulfur to form a sulfoxide or sulfone, respectively.

  As used herein, the terms “halo” and “halogen” refer to a halogen group, such as fluoro, chloro, bromo, or iodo.

In this specification, the term polyether means a group having two or more ether groups. The polyether may be, for example, a halo-substituted formula — (O (CH ₂ ) _a ) _b (CH ₂ ) _c CH ₃ , wherein a is 1, 2 or 3, and b is 2 3, 4 or 5 and c is 0, 1, 2, 3, 4 or 5].

  When n is an integer, the integer is preferably 1-20, more preferably 1-10, and even more preferably 1-6. For example, n is 1, 2, 3, 4, 5 or 6.

In this specification, reference to an “optionally substituted” group means that the group may be substituted with one or more substituents. For example, in certain embodiments, a group may be substituted with one or more alkyl, alkoxy, alkenyl, alkynyl, aryl, or heteroaryl groups. The group consists of halo, C ₁ -C ₁₀ alkyl and O (C ₁ -C ₁₀ alkyl), where the C ₁ -C ₁₀ alkyl group may be substituted with one or more halo groups. More preferably, it may be substituted with a substituent selected from the group. Halo is preferably fluoro. In certain embodiments, the group may be substituted with OTs. Even more preferably, the group may be substituted with one or more fluoro groups. One skilled in the art will readily appreciate that the compound of formula (III) or formula (IV) may be fluorinated at any position for subsequent radiolabeling.

In the framework of the present application, a compound according to the invention shall essentially contain all its stereochemical isomers. The term “stereochemical isomer” as used herein defines all possible stereochemical isomers that a compound of formula (III), (IV) or (V) may have. Unless otherwise stated or indicated, the chemical name of a compound represents a mixture of all possible stereochemical isomers, which includes all diastereomers and enantiomers of the basic molecular structure. . Further, in particular, the stereocenter may have an R- or S-configuration; a substituent of a divalent cyclic (partial) saturated group may have either a cis or trans configuration. A compound that includes a double bond may have E or Z stereochemistry at the double bond. Accordingly, all stereochemical isomers of the compounds of formula (III), (IV) or (V) are intended to be included within the scope of the present invention. In the present specification, the notation “ ^* ” represents the presence of a stereocenter.

  The inventors have surprisingly found that the compounds of formulas (III) and (IV), radiolabeled with radioisotopes, are selective TSPO ligands, and TSPO, and therefore the precise inactivation of microglia activation. It was found that it can be used as a vivo marker. Accordingly, these radiolabeled compounds may be used to study neuropathological events in several neurodegenerative disorders, and they may be used for the diagnosis of such disorders and It may be used as a tool for monitoring the progress of such a failure.

We have found that compounds of formula (III) with 6,8-dimethyl substitution are particularly selective TSPO ligands. That is, the compound of formula (III) in which R ¹⁹ and R ²¹ are methyl and R ²⁰ is H shows a high binding affinity for TSPO.

The radioisotope can be selected from any suitable radioisotope known to the skilled recipient, for example, Handbook of Radiopharmaceuticals, Radiochemistry Applications, Michael Welsch and Carol S. Edited by Redvanly, John Wiley & Sons Ltd 2003; and PET Chemistry, The Driving Force for Molecular Imaging. P. A. Schubiger, L.M. Lehmann, M.M. Examples include the radioisotopes listed in Friebe ed., Springer 2007. Radioisotopes include, but are not limited to, ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I, and ⁷⁵ Br and ¹¹ C.

In this ^{specification,} 18 A ^{F, 123 I, 76 Br,} 124 I and ⁷⁵ "radiolabelled" in Br compound of (III) or (IV), any substituents on the ^{compounds, 18} F , ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br. For example, at least one of R ^{12 to} R ³⁶ in formula (III) or (IV) may be substituted with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I, or ⁷⁵ Br. Typically, one of R ¹² -R ³⁶ is substituted with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br.

Usually, when a compound of formula (III) or (IV) is radiolabeled with ¹⁸ F, ⁷⁶ Br, ¹²⁴ I and or ⁷⁵ Br, an image is obtained by positron emission tomography (PET) imaging. It is done. Typically, when a compound of formula (III) or (IV) is radiolabeled with ¹²³ I, an image is obtained by single photon emission computed tomography (SPECT) imaging.

  There are several classes of TSPO ligands described in the literature. Compounds that are effective as therapeutic agents are not necessarily compounds that can be radiolabeled and used for imaging. In fact, many drugs used therapeutically are not selective for a particular target and can interact with several targets to produce a therapeutic effect. Furthermore, many therapeutic agents do not typically have the nM range of affinity used for imaging, but have the μM range of affinity. Furthermore, the metabolism and lipophilicity of the therapeutic agent can make the drug unsuitable for use for imaging, particularly when administered at the tracer level for imaging.

The inventors surprisingly used a compound of formula (III) or (IV) radiolabeled with a radioisotope selected from ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br. It has now been found that TSPO and thus microglial activation may be imaged in the subject. Compounds of formula (III) or (IV) radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br are selective ligands for TSPO and have high affinity for TSPO.

Compounds of (III) and (IV) radiolabeled with a radioisotope selected from ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br form a salt, and the salt of such compound is Included by the present invention. The salt is preferably pharmaceutically acceptable, but it should be understood that salts that are not pharmaceutically acceptable are also within the scope of the present invention. Examples of pharmaceutically acceptable salts include pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium salts; pharmaceutically acceptable inorganic acids such as Acid addition salts of hydrochloric acid, orthophosphoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid; or pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, Maleic acid, hydroxymaleic acid, fumaric acid, citric acid, lactic acid, mucoic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, trihalomethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid , Sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, Michin acid, oleic acid, lauric acid, pantothenic acid, tannic acid, salts of ascorbic acid and valeric.

Compounds of formula (III) or (IV) are used in organic chemistry to modify organic compounds to replace hydrogen or halo groups in the compounds with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br. It may be radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br by known standard techniques.

Alternatively, the compound of formula (III) or (IV) radiolabeled with a radioisotope selected from ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br is a compound of formula (III) or (IV) By incorporating ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br as substituents in one of the starting materials, or in an intermediate, eg, an intermediate compound of formula (V), used in the synthesis of May be prepared.

A compound of formula (III) or (IV) radiolabeled with ¹⁸ F, ¹²³ I _, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br is, for example, as defined above, but any one of R ^{12 to} R ³⁶ Having one of the formulas (III) or (IV), one of which is substituted with a leaving group such as tosylate, mesylate, Br or I, thereby allowing an aliphatic nucleophilic substitution reaction to take place at the leaving group And then subjecting the compound to conditions under which an aliphatic nucleophilic substitution reaction occurs and the leaving group is replaced with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br. Also good. For example, if the leaving group is Br or tosylate, the compound is reacted with [ ¹⁸ F] -kryptofix-K222 complex in acetonitrite at about 80 ° C. for 10 minutes to emit at ¹⁸ F. Labeled compounds of formula (III) or (IV) may be formed.

Compounds of formula (III) or (IV) radiolabeled with ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br are also as defined above, but one of R ^{12 to} R ³⁶ is stannyl, silyl or Forming a compound having the formula (III) or (IV) that is substituted with a halogen (the halogen substituent is usually different from the radioisotope), Subjecting it to an electrophilic substitution reaction using an oxidizing agent such as chloramine-T to form a compound of formula (III) or (IV) radiolabeled with ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br. May be formed. In some embodiments, the reaction may be performed at room temperature, and in other embodiments, the reaction mixture is heated to about 80 ° C to 100 ° C. A compound of formula (III) or (IV), as defined above, wherein one of R ¹² -R ³⁶ is substituted with a leaving group, the compound of formula (III) or (IV) is represented by one of R ¹² -R ³⁶ It may be modified by reactions known in organic chemistry for incorporation as a substituent above.

  For example, in certain embodiments, a compound of formula (III) or (IV) may be radiolabeled with a phenyl substituent via an ethoxy group using a tosyl or fluoro precursor, or an acetamide functional group May be directly labeled by using tosyl or fluoro precursors.

Compounds of formula (III) or (IV) have ¹⁸ F (half-life 110 minutes), ¹²³ I (half-life 13.2 hours), ⁷⁶ Br (half-life 16.2 hours), ¹²⁴ I (half-life 4. 2 days) or ⁷⁵ Br (half-life 1.6 hours). Usually, the compound of formula (III) or (IV) is radiolabeled with ¹⁸ F. Compounds of formula (III) or (IV) radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br can be performed in multiple scans in one day, so clinical implications for imaging Are more practical than compounds radiolabeled with radioisotopes having a considerably shorter half-life. In addition, hospitals / institutions that do not have a cyclotron in the facility can use such radioligands, which are prepared off-site without significant loss of activity during transport. This is because it can be transported to a hospital / institution. In addition, longer scans (eg, 180 minutes) can be performed using compounds labeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I, or ⁷⁵ Br, which means that they can be used in most organisms. To make it more suitable for the study of scientific processes.

Compounds of formula (III) or (IV) radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I, or ⁷⁵ Br have high affinity and selectivity for TSPO and do not exhibit TSPO in a subject. May be used to image. Thus, TSPO may be studied in a subject using a compound of formula (III) or (IV) radiolabeled with ¹⁸ F, ¹²³ I _, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br.

In subjects with a neurodegenerative disorder, TSPO expression in the brain parenchyma is dramatically increased compared to subjects who do not have a neurodegenerative disorder. Accordingly, neurodegenerative disorders may be examined using compounds of formula (III) and (IV) radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br, and the progression of neurodegenerative disorders is diagnosed And may be used for monitoring. Neurodegenerative disorders that can be studied, diagnosed or monitored using these compounds include but are not limited to Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, multiple system atrophy, epilepsy, encephalopathy, stroke and Brain tumors. Each of these disorders is associated with neuronal damage or infection. Other disorders that can be studied, diagnosed or monitored using these compounds include, but are not limited to, glioblastoma, ischemic stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, cortical basal ganglia Degeneration, cancer, depression, autoimmunity, infections and neurodegenerative diseases.

According to the present invention, a compound of formula (III) or (IV) or a pharmaceutically acceptable radiolabeled thereof with a radioisotope selected from ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br Salt is administered to the subject. Where the compound of formula (III) or (IV) is radiolabeled with ¹⁸ F, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br, the position of the radioisotope in the subject and thus the TSPO in the subject Are obtained by positron emission tomography (PET) imaging using conventional techniques known in the art. If the compound is radiolabeled with ¹²³ I, an image of the position of the radioisotope in the subject is obtained by SPECT imaging using conventional techniques known in the art. Usually, for both PET and SPECT imaging, the data is either a compound of formula (III) or (IV) radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br or a pharmaceutically Acquire using conventional dynamic or list mode acquisition techniques, starting immediately after administration of the acceptable salt and continuing for about 40 minutes or more. Upon completion of data acquisition, the data is typically processed to provide a time series of 3D reconstructions, each representing the distribution of radioisotopes in the body at a particular point in time.

Usually, a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br is administered parenterally. Usually, a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br is administered parenterally by intravenous injection or infusion. Administer. Usually, a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof radiolabeled with ¹⁸ F, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br is in the range of about 5-20 mCi (185-740 MBq). At a dose of

Usually, a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof radiolabeled with ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br is ¹⁸ F, ¹²³ I, ⁷⁶ Br. Administering a pharmaceutical composition comprising a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof radiolabeled with ¹²⁴ I or ⁷⁵ Br and a pharmaceutically acceptable carrier. Be administered.

  Formulations for parenteral administration are usually in the form of sterile water or a non-aqueous solution, suspension or emulsion. Examples of suitable non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable aqueous carriers include water and alcoholic / aqueous solutions, emulsions or suspensions, such as saline and buffered media. Suitable parenteral vehicles include sodium chloride solution.

  It is preferred that the salt of the compound of formula (III) or (IV) is pharmaceutically acceptable, but it should be understood that salts that are not pharmaceutically acceptable are also within the scope of the present invention. Non-pharmaceutically acceptable salts of compounds of formula (III) or (IV) may also be used as intermediates in the preparation of pharmaceutically acceptable salts of compounds of formula (III) or (IV). Examples of pharmaceutically acceptable salts include pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium salts; pharmaceutically acceptable inorganic acids such as Acid addition salts of hydrochloric acid, orthophosphoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid and hydrobromic acid; or pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, Maleic acid, hydroxymaleic acid, fumaric acid, citric acid, lactic acid, mucoic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, trihalomethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid , Sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, Michin acid, oleic acid, lauric acid, pantothenic acid, tannic acid, salts of ascorbic acid and valeric.

  Compounds of formula (III) or (IV) are selective for TSPO and can activate TSPO. TSPO activation is associated with increased neurosteroid synthesis. Thus, activation of TSPO can increase the concentration of neurosteroids in the brain. These neurosteroids and their metabolites, including progesterone and dehydroepiandrosterone, positively regulate γ-aminobutyric acid (GABA) neurotransmission, which is a therapeutic benefit in memory and stress related disorders , Leading to an anti-anxiety effect. The compounds of formula (III) or (IV) may also be used as neuroprotective agents for the treatment of neurodegenerative disorders, as anti-inflammatory agents and as anxiolytic agents.

  Accordingly, in another aspect, the invention provides a method of treating a neurodegenerative disorder, inflammation or anxiety in a subject, wherein the subject has a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof. A method comprising administering a therapeutically effective amount of a prepared salt. Neurodegenerative disorders that can be treated by the present methods include Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, multiple system atrophy, epilepsy, encephalopathy, stroke and brain tumor. The compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof is usually administered as a pharmaceutical composition comprising a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof. Is administered.

  In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

  The composition of the present invention comprises at least one compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers, and optionally other Together with other treatments. Suitable compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The composition may be presented in unit dosage form and may be conveniently prepared by methods well known in the pharmaceutical art. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Typically, the composition comprises a compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof with a liquid carrier, diluent, adjuvant, and / or excipient, or a finely divided solid carrier or both. , Uniformly, closely related, and then, if necessary, prepared by molding the product.

  As used herein, the term “subject” refers to any animal. The subject can be a mammal, eg, a human. In some embodiments, the subject is a companion animal such as a dog or cat, a horse, a pony, a donkey, a mule, a llama, an alpaca, a domestic animal such as a pig, cow or sheep, or a primate, feline, dog A zoo animal such as a family animal, bovine or ungulate.

  As used herein, the term “therapeutically effective amount” refers to an amount of a compound that is effective to produce a desired therapeutic response. The specific “therapeutically effective amount” is the specific condition being treated, the condition of the subject, the type of subject being treated, the duration of treatment, the nature of the current treatment (if any), and the use Depending on factors such as the particular formulation being administered, the attending physician will be able to determine the appropriate therapeutically effective amount. For example, the attending physician will consider the appropriate dosage of the compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof in view of conventional dosages of other neurologically active compounds or the results of animal studies. A therapeutically effective amount can be determined. In some embodiments, the compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof may be administered at a dosage of about 1 to about 20 mg / kg body weight / day.

  As used herein, a “pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering a compound to a subject. The carrier can be in any form including solid, liquid or gas and is selected based on the planned method of administration. A carrier is “pharmaceutically acceptable” in the sense that it is not undesirable, whether biologically or not, that is, the carrier causes any or substantial adverse reaction to the subject. Without being administered with the active ingredient.

  The compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof is orally, topically or parenterally (eg by subcutaneous injection, by aerosol administration to the lungs or nasal cavity, or Intravenous, intramuscular, intrathecal or intracranial injection or infusion techniques) may be administered in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers.

  The compound of formula (III) or (IV) or a pharmaceutically acceptable salt thereof is a tablet, aqueous or oily suspension, lozenge, troche, powder, granule, emulsion, capsule, syrup or elixir. It may be administered orally as an agent. Compositions for oral use include sweeteners, flavoring agents, coloring agents, disintegrating agents, lubricants, time delay agents and storage to produce pharmaceutically refined and tasty formulations. One or more agents selected from the group consisting of agents may be included. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methyl cellulose, polyvinyl pyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavoring agents include peppermint oil, winter green oil, cherry, orange or raspberry flavors. Suitable preservatives include sodium benzoate, vitamin E, alpha tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

  Formulations for parenteral administration are usually in the form of a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of suitable non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable aqueous carriers include water and alcoholic / aqueous solutions, emulsions or suspensions such as saline and buffered media. Suitable parenteral vehicles include sodium chloride solution. Preservatives and other additives such as antibacterial agents, antioxidants, chelating agents, growth factors, inert gases and the like may also be present.

  In general, the terms “treating”, “treatment”, etc., as used herein mean affecting a subject to obtain a desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease or disorder or its signs or symptoms, and / or may be therapeutic in terms of partial or complete cure of the disease or disorder. As used herein, “treating” refers to any treatment or prevention of a disease or disorder in vertebrates, mammals, and particularly humans, and (a) may be susceptible to the disease or disorder, Preventing the occurrence of the disease or disorder in a subject that has not yet been diagnosed as having the disease or disorder, (b) inhibiting the disease or disorder, ie, stopping the progression of the disease or disorder, or (C) reducing or ameliorating the effect of the disease or disorder, i.e. causing a regression of the effect of the disease or disorder.

  Embodiments of the present invention are described below by reference to the following non-limiting examples.

Preparation of 6,8-dimethyl- [1,2,4] triazolo [4,3-b] pyridazine (1)

Scheme 1.
Method A
To a solution of 4-amino-1,2,4-triazole (1.00 g, 11.9 mmol) in EtOH (30 mL) was added 2,4-pentanedione (1.9 g, 11.9 mmol) at reflux. For 14 hours. The reaction mixture was allowed to cool and then the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane / MeOH, 20: 1 v / v as eluent) to give 1 (0.46 g, 26%) as pale yellow crystals; mp: 106- 109 ° C; ¹ H NMR (CDCl ₃ , 300 MHz) δ: 2.54 (s, 3H), 2.70 (s, 3H), 6.81 (s, 1H), 8.98 (s, 1H) .

Method B
To a solution of 4-amino-1,2,4-triazole (5 g, 60 mmol) in anhydrous toluene (25 mL) was added 2,4-pentanedione (6.0 g, 60 mmol) and p-toluenesulfonic acid (0. 06 g, 0.35 mmol) and heated at reflux using a Dean Stark trap for 7 hours. When the reaction was complete, the resulting yellow clear solution was allowed to cool to room temperature and evaporated to dryness. The crude oil was dissolved in CHCl ₃ and washed with saturated aqueous NaHCO ₃ solution. The organic layer was isolated, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness to give pure product 1 (7.65 g, 87%) as pale yellow crystals. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 2.54 (s, 3H), 2.70 (s, 3H), 6.81 (s, 1H), 8.98 (s, 1H).

Preparation of 6,8-dimethyl-2- (2-oxo-2-phenylethyl)-[1,2,4] triazolo [4,3-b] pyridazine-2-ium (2)

Scheme 2.
To a solution of 1 (2.00 g, 13.5 mmol) in nitromethane (35 mL) was added bromoacetophenone (2.70 g, 13.5 mmol) and heated at reflux for 2.5 hours under an inert atmosphere. The reaction mixture was allowed to cool and the solvent was evaporated to dryness to give a red sticky oil. The crude oil was purified by silica gel column chromatography (CHCl ₃ / MeOH, 7: 1 (v / v) as eluent) to give 2 (2.7 g, 75%) as orange crystals; : 189-192 ° C. ¹ H NMR (CDCl _3, 300 MHz) δ: 2.70 (s, 6H), 6.98 (s, 2H), 7.28 (d, J = 1.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.69 (tt, J = 1.2, 7.4 Hz, 1H), 8.08 (d, J = 1.2 Hz, 2H), 11.89 (s, 1H) ). Mass spectrum: Cl, m / z 268 (M + 1).

Preparation of 4,6-dimethylpyridazine-3-amine (3)

Scheme 3.
A solution of alkylated salt 2 (2.58 g, 9.65 mmol) in 20% aqueous NaOH (29.0 mmol) was heated at reflux for 16 hours. The crude reaction mixture was evaporated to dryness and purified by silica gel column chromatography (CHCl ₃ / MeOH as eluent, 10: 1 (v / v)) to give 3 (1.1 g, 93%) as a light brown powder. Obtained; melting point: 123-126 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 2.13 (s, 3H), 2.50 (s, 3H), 6.93 (s, 1H). Mass spectrum: Cl, m / z 124 (M + 1).

General procedure for the synthesis of compounds 4a-e

Scheme 4.
A solution of the appropriate oxobutanoic acid (24 mmol), diethylamine (2.70 mL, 26.4 mmol), triethylamine (13 mL, 36 mmol) and EEDQ (7.20 g, 28.8 mmol) in anhydrous THF (100 mL) at reflux. Heated overnight. The reaction mixture was allowed to cool and the solvent was removed in vacuo. The remaining residue was acidified with dilute HCl (10%) and then neutralized with dilute NaOH (5%). The neutral solution was washed with water and extracted with CHCl ₃ . The organic layer was dried over Na ₂ SO ₄ and evaporated to give a dark red oil. The oil was cooled to 0 ° C. Ethyl acetate (30 mL) was added to the cooled oil and the resulting crystals were filtered and washed with petroleum ether to give the corresponding amide product.

Preparation of N, N-diethyl-4- (4-methoxyphenyl) -4-oxobutanamide (4a)

This compound was obtained from 4- (4-methoxyphenyl) -4-oxobutanoic acid (5.0 g, 24 mmol) as pale yellow crystals; 5.2 g, 83%; melting point: 59-62 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.09-1.26 (m, 6H), 2.76 (t, J = 6.9 Hz, 2H), 3.30-3.41 (m, 6H) ), 3.87 (s, 3H), 6.93 (d, J = 9.0 Hz, 2H), 8.00 (d, J = 9.0 Hz, 2H).

Preparation of N, N-diethyl-4-oxo-4-p-tolylbutanamide (4b)

This compound was obtained from 4-oxo-4-p-tolylbutanoic acid (4.6 g, 24 mmol) as pale yellow crystals; 4.7 g, 80%; melting point: 63-66 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.08-1.26 (m, 6H), 2.41 (s, 3H), 2.76 (t, J = 6.9 Hz, 2H), 3. 30-3.42 (m, 6H), 7.25 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H).

Preparation of 4- (4-chlorophenyl) -N, N-diethyl-4-oxobutanamide (4c)

This compound was obtained as 4-brown crystals from 4- (4-chlorophenyl) -4-oxobutanoic acid (5.1 g, 24 mmol); 5.3 g, 83%; melting point: 85-88 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.08-1.26 (m, 6H), 2.77 (t, J = 6.6 Hz, 2H), 3.30-3.43 (m, 6H) ), 7.43 (d, J = 6.9 Hz, 2H), 7.96 (d, J = 6.9 Hz, 2H).

Preparation of 4- (4-bromophenyl) -N, N-diethyl-4-oxobutanamide (4d)

This compound was obtained from 4- (4-bromophenyl) -4-oxobutanoic acid (6.2 g, 24 mmol) as shiny, white crystals; 6.0 g, 80%; melting point: 90-93 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.08-1.26 (m, 6H), 2.77 (t, J = 6.6 Hz, 2H), 3.29-3.43 (m, 6H) ), 7.59 (d, J = 6.6 Hz, 2H), 7.89 (d, J = 6.6 Hz, 2H).

Preparation of N, N-diethyl-4- (4-fluorophenyl) -4-oxobutanamide (4e)

This compound was obtained from 4- (4-fluorophenyl) -4-oxobutanoic acid (4.7 g, 24 mmol) as dark orange crystals; 5.1 g, 85%; melting point: 48-51 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.08-1.26 (m, 6H), 2.78 (t, J = 6.6 Hz, 2H), 3.30-3.44 (m, 6H) ), 7.09-7.15 (m, 2H), 8.02-8.07 (m, 2H).

General Procedure for the Synthesis of Compound 5a-e At 0 ° C. to a solution of the appropriate amide 4a-e (7.6 mmol) in CHCl ₃ (˜20 mL), bromine (0.4 mL, 7.6 mmol). Slowly added and stirred for 1 hour. The reaction was then stirred overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50:50 (v / v) as eluent) to give the respective brominated product.

Scheme 5. (I) TEA, diethylamine, THF, EEDQ, reflux 12 hours; (ii) Br ₂ , CHCl ₃ , 1 hour at 0 ° C., overnight at room temperature; (iii) DMF, reflux 24 hours.

Preparation of 3-bromo-N, N-diethyl-4- (4-methoxyphenyl) -4-oxobutanamide (5a)

Pale yellow oil obtained from 4a (2 g, 7.6 mmol); 2.47 g, 95%. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.05-1.29 (m, 6H), 3.00-3.58 (m, 6H), 3.87 (s, 3H), 5.62- 5.78 (m, 1H), 6.95 (d, J = 9.0 Hz, 2H), 8.04 (d, J = 9.0 Hz, 2H).

Preparation of 3-bromo-N, N-diethyl-4-oxo-4-p-tolylbutanamide (5b)

Yellow oil obtained from 4b (1.88 g, 7.6 mmol); 1.9 g, 78%. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.04-1.29 (m, 6H), 2.41 (s, 3H), 3.01-3.59 (m, 6H), 5.65- 5.79 (m, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H).

Preparation of 3-bromo-4- (4-chlorophenyl) -N, N-diethyl-4-oxobutanamide (5c)

Fluorescent green oil obtained from 4c (2.0 g, 7.6 mmol); 2.36 g, 90%. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.04-1.29 (m, 6H), 3.01-3.62 (m, 6H), 5.59-5.67 (m, 1H), 7.46 (d, J = 8.7 Hz, 2H), 7.9 (d, J = 8.7 Hz, 2H).

Preparation of 3-bromo-4- (4-bromophenyl) -N, N-diethyl-4-oxobutanamide (5d)

Pale yellow oil obtained from 4d (3.75 g, 12 mmol); 4.12 g, 88%. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.04-1.28 (m, 6H), 3.01-3.61 (m, 6H), 5.56-5.61 (m, 1H), 7.60-7.64 (m, 2H), 7.89-7.94 (m, 2H).

Preparation of 3-bromo-N, N-diethyl-4- (4-fluorophenyl) -4-oxobutanamide (5e)

Pale yellow oil obtained from 4e (1.58 g, 6.2 mmol); 1.72 g, 84%. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.04-1.29 (m, 6H), 3.01-3.62 (m, 6H), 5.92-5.64 (m, 1H), 7.12-7.26 (m, 2H), 8.06-8.12 (m, 2H).

General Procedure for the Synthesis of Compound 6a-e A mixture of 3 (6.18 mmol) in anhydrous DMF (10 mL) with a brominated amide 5a-e (6.18 mmol) in anhydrous DMF (10 mL). And heated at reflux under an inert atmosphere for 24 hours. The crude reaction mixture was allowed to cool, evaporated to dryness and purified by silica gel column chromatography using ethyl acetate as eluent to give the corresponding dimethylimidazopyridazine.

Preparation of N, N-diethyl-2- (2- (4-methoxyphenyl) -6,8-dimethylimidazo [1,2-b] pyridazin-3-yl) ethanamide (6a)

Light brown crystals obtained from 5a (2.1 g, 6.18 mmol); 1.2 g, 54%, melting point: 129-131 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.16 to 1.32 (m, 6H), 2.50 (s, 3H), 2.65 (s, 3H), 3.42 to 3.58 ( m, 4H), 3.84 (s, 3H), 4.11 (s, 2H), 6.71 (s, 1H), 6.98 (d, J = 8.7 Hz, 2H), 7.79. (D, J = 8.7 Hz, 2H); found: C, 65.05; H, 6.30; N, 14.18. Mass spectrum: Cl, m / z 367 (M + 1).

Preparation of 2- (6,8-dimethyl-2-p-tolylimidazo [1,2-b] pyridazin-3-yl) -N, N-diethylethanamide (6b)

Light brown crystals obtained from 5b (1.0 g, 2.9 mmol); 0.50 g, 50%, melting point: 155-158 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.13-1.32 (m, 6H), 2.39 (s, 3H), 2.43 (s, 3H), 2.64 (s, 3H) 3.44-3.55 (m, 4H), 4.12 (s, 2H), 6.70 (s, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.72. (D, J = 8.2 Hz, 2H); found: C, 63.58; H, 6.92; N, 13.92. Mass spectrum: Cl, m / z 351 (M + 1).

Preparation of 2- (2- (4-chlorophenyl) -6,8-dimethylimidazo [1,2-b] pyridazin-3-yl) -N, N-diethylethanamide (6c)

Light brown crystals obtained from 5c (0.95 g, 2.9 mmol); 0.57 g, 53%, melting point: 162-165 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.13 to 1.34 (m, 6H), 2.50 (s, 3H), 2.64 (s, 3H), 3.44 to 3.57 ( m, 4H), 4.11 (s, 2H), 6.73 (s, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H); found: C, 63.46; H, 6.30; N, 14.49. Mass spectrum: Cl, m / z 371 (M + 1).

Preparation of 2- (2- (4-bromophenyl) -6,8-dimethylimidazo [1,2-b] pyridazin-3-yl) -N, N-diethylacetamide (6d)

Light brown crystals obtained from 5d (1.00 g, 2.6 mmol); 0.55 g, 51%, melting point: 171-175 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.13 to 1.34 (m, 6H), 2.50 (s, 3H), 2.64 (s, 3H), 3.42 to 3.60 ( m, 4H), 4.10 (s, 2H), 6.72 (s, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H); Found: C, 57.47; H, 5.50; N, 12.87. Mass spectrum: Cl, m / z 415 (M + 1).

Preparation of N, N-diethyl-2- (2- (4-fluorophenyl) -6,8-dimethylimidazo [1,2-b] pyridazin-3-yl) acetamide (6e)

Light brown crystals obtained from 5e (0.67 g, 1.7 mmol); 0.33 g, 55%, melting point: 139-143 ° C. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.13 to 1.34 (m, 6H), 2.50 (s, 3H), 2.64 (s, 3H), 3.42 to 3.60 ( m, 4H), 4.10 (s, 2H), 6.71 (s, 1H), 7.10-7.16 (m, 2H), 7.82-7.87 (m, 2H); Value: C, 67.29; H, 6.60; N, 14.99. Mass spectrum: Cl, m / z 355 (M + 1).

Preparation of N, N-diethyl-2- (2- (4-hydroxyphenyl) -6,8-dimethylimidazo [1,2-b] pyridazin-3-yl) ethanamide (7)

Scheme 6.
Method A
At 0 ° C., BBr ₃ (2.87 mL, 2.87 mmol) was added dropwise to a solution of methoxypyridazine 6a (0.7 g, 1.9 mmol) in anhydrous dichloromethane (40 mL). After stirring at 0 ° C. for 1 hour, an additional 1.5 equivalents of BBr ₃ (2.87 mL, 2.87 mmol) was added dropwise and the mixture was stirred at room temperature for 16 hours. After this time, the reaction mixture was quenched with MeOH (˜20 mL) and evaporated to dryness. The resulting brown solid was washed with CHCl ₃ and purified by column chromatography (eluent; dichloromethane / MeOH, 10: 1 v / v) to give 7 (0.49 g, 1.4 mmol) 73% Obtained as a tan powder in a yield of mp 266-268 ° C. ¹ H NMR (DMSO, 300 MHz) δ: 1.01-1.26 (m, 6H), 2.44 (s, 3H), 2.53 (s, 3H), 3.24-3.55 (m , 4H), 4.08 (s, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.94 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H) ); Found: C, 63.40; H, 6.59; N, 13.59. Mass spectrum: Cl, m / z 353 (M + 1).

Method B
A solution of methoxypyridazine 6a (0.25 g, 0.68 mmol), hexadecyltributylphosphonium bromide (0.023 g, 0.068 mmol) and 45% HBr (4.5 mL) was heated at 100 ° C. with constant stirring for 7 hours. did. The reaction mixture was basified to pH 8-9 using NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was collected and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under vacuum and the residue was purified by column chromatography to give 7.

2- (4- (3- (2- (diethylamino) -2-oxoethyl) -6,8-dimethylimidazo [1,2-b] pyridazin-2-yl) phenoxy) ethyl 4-methylbenzenesulfonate (8 Preparation of

Method A
To a solution of 7 (176 mg, 0.5 mmol) triphenylphosphine (285 mg, 1.1 mmol) and toluene-4-sulfonic acid 2-hydroxy-ethyl ester (235 mg, 1.1 mmol) in anhydrous DMF (10 mL) was added diisopropyl. Azodicarboxylate (DIAD, 0.21 mL, 1.1 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours and then concentrated in vacuo (95 ° C., 20 mbar). The resulting crude oil was dissolved in CHCl ₃ (40 mL) and washed with water (3 × 20 mL) to remove traces of DMF. The organic layer was isolated and dried over anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by column chromatography (CHCl ₃ / MeOH, 80: 1 v / v as eluent) to give 8 (10 mg, 0.018 mmol) as a pale yellow in 4% yield. Obtained as crystals. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.13 to 1.28 (m, 6H), 2.45 (s, 3H), 2.49 (s, 3H), 2.63 (s, 3H) 3.44-3.58 (m, 4H), 4.10 (s, 2H), 4.16-4.20 (m, 2H), 4.37-4.40 (m, 2H), 6 .70 (s, 1H), 6.85 (d, J = 6.9 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 6.9 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H).

Method B
Sodium hydride (0.05 g, 60% dispersion in oil, 1.25 mmol) in anhydrous DMF (˜7 mL) was added to 7 (0.175 g, 0.50 mmol) in anhydrous DMF (˜7 mL). The solution was added. After stirring at 0 ° C. for 1 hour, ethylene glycol di-p-tosylate (0.736 g, 2 mmol) was dissolved in anhydrous DMF (˜2 mL) and slowly added to the main reaction solution. The mixture was then allowed to stir at room temperature for 12 hours, after which the solution was concentrated in vacuo (95 ° C., 20 mbar). The resin thus obtained was extracted with dichloromethane and washed twice with a saturated aqueous solution of ammonium chloride. The organic layer was then washed 4 times with water (removing any remaining DMF), dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting crude oil was purified by column chromatography using ethyl acetate as eluent to give 8 (130 mg, 0.24 mmol) as yellow crystals in 47% yield; melting point: 120 ˜123 ° C .; ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.13-1.28 (m, 6H), 2.45 (s, 3H), 2.49 (s, 3H), 2.63 ( s, 3H), 3.42-3.58 (m, 4H), 4.10 (s, 2H), 4.16-4.20 (m, 2H), 4.37-4.40 (m, 2H), 6.70 (s, 1H), 6.85 (d, J = 6.9 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 6.9 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H); measured values: C, 63.06; H, 6. 44; N, 10.12. Mass spectrum: Cl, m / z 551 (M + 1).

Preparation of 2-fluoroethyl-4-methylbenzenesulfonate

A solution of pyridine (17 mL, 0.21 mol), p-toluenesulfonyl chloride (3.57 g, 18.73 mmol) and fluoroethanol (1 mL, 17.03 mmol) was added at 0 ° C. for 1 hour under argon and further at room temperature. For 14 hours. The pale clear mixture was quenched with ice water (˜30 mL) and shaken for 5 minutes to hydrolyze any unreacted tosyl chloride. The suspension was extracted with ethyl acetate (˜15 mL) and excess pyridine was neutralized by adding dilute sulfuric acid (containing crushed ice) to the organic layer. The organic layer was then washed and washed with additional dilute sulfuric acid (containing crushed ice), ice water, dilute potassium hydroxide (containing crushed ice), and again with ice water. After this time, the ether solution was dried over anhydrous sodium sulfate and the solvent removed in vacuo to give 2-fluoroethyl-4-methylbenzenesulfonate (1.40 g, 6.41 mmol) as a clear, 38% yield. Obtained as an oil. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 3.58 (s, 3H), 4.19-4.31 (m, 2H), 4.47-4.66 (m, 2H), 7.36 ( d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H).

N, N-diethyl-2- (2- (4- (2-fluoroethoxy) phenyl) -6,8-dimethylimidazo- [1,2-b] pyridazin-3-yl) ethanamide (9, PDAZ-FE Preparation of

Method A
To a solution of 7 (150 mg, 0.43 mmol), triphenylphosphine (274 mg, 0.94 mmol) and 2-fluoroethanol (60 mg, 0.94 mmol) in anhydrous DMF (6 mL) was added diisopropyl azodicarboxylate (DIAD, 190 mg, 0.94 mmol) was added. The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo (95 ° C., 20 mbar). The resulting crude oil was dissolved in CHCl ₃ (40 mL) and washed with water (3 × 20 mL) to remove traces of DMF. The organic layer was isolated and dried over anhydrous Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was purified by column chromatography (CHCl ₃ / MeOH, 80: 1 v / v as eluent) to give 9 (15 mg, 0.038 mmol) as a pale yellow in 9% yield. Was obtained as a crystal. ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.13-1.32 (m, 6H), 2.49 (s, 3H), 2.64 (s, 3H), 3.42-3.58 ( m, 4H), 4.11 (s, 2H), 4.26 (dt, J = 4, 28 Hz, 2H), 4.78 (dt, J = 4, 47 Hz, 2H), 6.70 (s, 1H), 7.01 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H).

Method B
To a solution of 7 (0.20 g, 0.57 mmol) in anhydrous DMF (˜7 mL) to sodium hydride (0.046 g, 60% dispersion in oil, 1.14 mmol) in anhydrous DMF (˜7 mL). added. After stirring at 0 ° C. for 1 hour, a solution of 2-fluoroethyl-4-methylbenzenesulfonate (0.125 g, 0.57 mmol) in anhydrous DMF (˜2 mL) was slowly added to the main reaction solution. The mixture was then allowed to stir at room temperature for 12 hours, after which the solution was concentrated in vacuo (95 ° C., 20 mbar). The resin was extracted with dichloromethane and washed twice with a saturated solution of ammonium chloride. The organic layer was then washed 4 times with water (removing any remaining DMF), dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting crude oil was purified by column chromatography using ethyl acetate as eluent to give 9 (130 mg, 0.33 mmol) as yellow crystals in 58% yield; mp: 149- 151 ° C; ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.13-1.32 (m, 6H), 2.49 (s, 3H), 2.64 (s, 3H), 3.42-3 .58 (m, 4H), 4.11 (s, 2H), 4.26 (dt, J = 4, 28 Hz, 2H), 4.78 (dt, J = 4, 47 Hz, 2H,), 6. 70 (s, 1H), 7.01 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H); measured values: C, 66.68; H, 7. 03; N, 14.07. Mass spectrum: Cl, m / z 399 (M + 1).

2. Synthesis of carboxylic acid intermediates

_{R = OH, CH 3, OCH} 3, NO 2, F, Cl, naphthyl; R '= H, Cl; X = N, CH.

Scheme 7: _{Reagents: (a) EtOH, H 2} SO 4 (b) N- bromosuccinimide, dibenzoyl peroxide (c) 2,5-dimethoxytetrahydrofuran, glacial acetic acid (d) NaH (e) 10 % NaOH.

General Procedure for the Synthesis of Compounds 10-16 The appropriate phenylacetic acid 10 was dissolved in absolute ethanol and refluxed in the presence of a catalytic amount of sulfuric acid to produce the ethyl ester 11. The ethyl ester was then refluxed in chloroform for 24 hours using an equimolar amount of freshly recrystallized N-bromosuccinimide and a catalytic amount of benzoyl peroxide to produce α-bromo-aryl ester 12. Produce pyrrole 14 by refluxing the appropriate aminophenol 13 in glacial acetic acid for 4 hours using a molar equivalent of 2,5-dimethoxytetrahydrofuran (mixture of cis- and trans-isomers). (Or may be prepared from aminopyridinol). The pyrrole 14 was then deprotonated at the hydroxyl position by using sodium hydride in anhydrous tetrahydrofuran (THF) for 1 hour at 0 ° C. followed by equimolar amounts of α-bromo-aryl ester in anhydrous THF. 12 was coupled overnight to produce ethyl ester-acetamide 15. Hydrolysis of ethyl ester 15 to the corresponding acid 16 was accomplished using 10% sodium hydroxide solution in ethanol / THF (1: 1) and stirring at room temperature for 2 hours.

(4-Methoxy-phenyl)-(2-pyrrol-1-yl-pyridin-3-yloxy) -acetic acid (16a)

MS-ESI: m / z 325.1 (99%, M + 1). ¹ H-NMR (CD ₃ OD) δ 3.84 (3H, s), 5.89 (1H, s), 6.31 (2H, t, J = 2.4 Hz), 6.96 (2H, d, J = 9 Hz), 7.22 (1H, q), 7.50 (2H, d, J = 9 Hz), 7.57 (1H, d), 7.74 (2H, t, J = 2.4 Hz) , 8.06 (1H, dd).

(4-Methoxy-phenyl)-(2-pyrrol-1-yl-phenoxy) -acetic acid (16b)

MS-ESI: m / z 323.9 (50%, M + 1). ¹ H-NMR (CDCl ₃ ) δ 3.79 (3H, s), 5.43 (1H, s), 6.34 (2H, t), 6.88 (2H, d, J = 8.7 Hz), 6.97 (1H, d, J = 2.3 Hz), 7.06 (2H, t), 7.07 (1H, s), 7.21 (1H, d, J = 2.3 Hz), 7. 35 (2H, d, J = 8.7 Hz), 7.36 (1H, s). CHN analysis value C (calculated value 70.58, measured value 67.34), H (calculated value 5.30, measured value 5.39), N (calculated value 4.33 measured value 4.12).

(4-Fluoro-phenyl)-(2-pyrrol-1-yl-phenoxy) -acetic acid (16c)

MS-ESI: m / z 310.3 (30%, M-1). ¹ H-NMR (CDCl ₃ ) δ 5.46 (1H, s), 6.33 (2H, t), 6.96 (1H, dd), 7.03-7.05 (3H, m), 7. 10 (1H, dd), 7.20 (1H, dd), 7.34 (1H dd), 7.38-7.44 (3H, m). CHN analysis value C (calculated value 69.45, measured value 67.27), H (calculated value 4.53, measured value 4.53), N (calculated value 4.50 measured value 3.84).

(4-Chloro-2-pyrrol-1-yl-phenoxy)-(4-methoxy-phenyl) -acetic acid (16d)

MS-ESI: m / z 379.9 (99%, M + 1, as sodium salt). ¹ H-NMR (CDCl ₃ ) δ 3.79 (3H, s), 5.38 (1H, s), 6.31 (2H, t), 6.85 (2H, d, J = 9 Hz), 7. 01 (1H, d), 7.05 (2H, t), 7.14 (1H, dd), 7.24 (2H, d, J = 9 Hz), 7.31 (1H, d).

3. Synthesis of acetamide ligand

_{R = OH, CH 3, OCH} 3, NO 2, F, Cl, naphthyl; R '= H, Cl; X = N, CH.

  Scheme 8: Acetamide synthesis. Reagent: EEDQ, TEA, DEA.

General Procedure for the Synthesis of Acetamide Compound 19 Carboxylic acid 16 is dissolved in anhydrous THF, to which is added excess initiator 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), triethylamine and diethylamine. Was added. The reaction was refluxed for 8-12 hours and the completion of the reaction was monitored by TLC to produce acetamide 19.

N, N-diethyl-2- (4-methoxy-phenyl) -2- (2-pyrrol-1-yl-pyridin-3-yloxy) -acetamide (19a)

MS-ESI: m / z 380.0 (35%, M + 1). ¹ H-NMR (CDCl ₃ ) δ 0.88 (3H, t), 1.09 (3H, t), 3.20 (2H, q), 3.35 (2H, q), 3.80 (3H, s), 5.65 (1H, s), 6.30 (2H, t), 6.89 (2H, d, J = 8.7 Hz), 7.05 (1H, dd), 7.33 (1H) M), 7.32 (2H, d, J = 8.7 Hz), 7.65 (2H, t), 8.11 (1H, dd).

N, N-diethyl-2- (4-methoxy-phenyl) -2- (2-pyrrol-1-yl-phenoxy) -acetamide (19b)

MS-ESI: m / z 378.3 (25%, M). ¹ H-NMR (CDCl ₃ ) δ 0.75 (3H, t), 1.05 (3H, t), 3.21 (2H, q), 3.31 (2H, q), 3.79 (3H, s), 5.61 (1H, s), 6.32 (2Hmt), 6.84 (2H, d, J = 9 Hz), 7.05 (2H, t), 7.22 (1H, m) 7.27 (1H, s), 7.31 (2H, d), 7.34 (2H, m).

2- (4-Chloro-2-pyrrol-1-yl-phenoxy) -N, N-diethyl-2- (4-methoxy-phenyl) -acetamide (19d)

MS-ESI: m / z 412.3 (92%, M). ¹ H-NMR (CDCl ₃ ) δ 0.85 (3H, t), 1.05 (3H, t), 3.10 (2H, q), 3.76 (2H, q), 3.88 (3H, s), 5.50 (1H, s), 6.32 (2H, t), 6.86 (3H, dd), 7.06 (2H, t), 7.17 (1H, d), 7. 22, (1H, s), 7.31 (1H, d), 7.44 (1H, d).

  Of course, it is well within the ability of one skilled in the art to synthesize compounds of formula (IV) with slight modifications to the above parameters. For example, by changing the appropriate starting reagents by changing the reaction time, temperature, molar ratio. Additional compounds synthesized by this route include:

および

and

Other compounds of particular interest include:

4). Resolution of chiral carboxylic acid 16 Med. Chem. 1991, Vol. 34, No. 9, 2864. The resolved carboxylic acid 16 can be converted to acetamide by a general procedure for the synthesis of acetamide compound 19 as illustrated in Schemes 8 and 9.

_{R = OH, CH 3, OCH} 3, NO 2, F, Cl, naphthyl; R '= H, Cl; X = N, CH;

または

R '' =

Or

  Scheme 9: Reagent (a) Oxalyl chloride, N-methylpyrrolidine, (R)-(−)-pantolactone or D-(+)-ribbonic acid-γ-lactone (b) 2N HCl, AcOH (c) EEDQ, DEA, TEA.

5. In Vitro binding affinity 3H-PK11195 (specific activity 322 GBq / mmol) and 3H-Ro 15-1788 (specific activity 311 GBq / mmol) were purchased from Dupont-New England Nuclear. For binding studies, Trapani G. et al. J Med Chem. 1997; 40: 3109-3118, but with minor modifications as described herein, mitochondria were prepared from kidneys of male Wistar rats sacrificed by cervical dislocation. . 20 volumes of ice-cold 50 mM Tris- containing a protease inhibitor (160 mg / mL benzamidine, 200 mg / mL bacitracin and 20 mg / mL soybean trypsin inhibitor) in a glass homogenizer using a Teflon inner tube Kidneys were homogenized in HCl (pH 7.4), 0.32 M sucrose and 1 mM ethylenediaminetetraacetic acid (buffer A) and centrifuged at 4 ° C. and 600 g for 10 minutes. The resulting supernatant was centrifuged at 10,000 g for 10 minutes at 4 ° C. The pellet was suspended in 20 volumes of ice cold buffer A and centrifuged at 10,000 g for 10 minutes at 4 ° C. The crude mitochondrial pellet is frozen at −20 ° C. until the time of the assay, or 50 mM Tris-HCl (pH 7.4) containing various concentrations of test compound (0.1 nM to 10 mM) in a total volume of 0.5 mL. (Buffer B) was incubated with 0.6 nM 3H-PK11195 at 4 ° C. for 90 minutes. Incubation was terminated by diluting to 5 mL with ice cold buffer B and this step was immediately followed by rapid filtration through glass fiber Whatman GF / C filters. The filter was washed with buffer B (2.5 mL) and the amount of radioactivity retained on the filter was determined using a Packard 1600TR liquid scintillation counter with 66% efficiency. Nonspecific binding was estimated for each sample in the presence of unlabeled 1 mM PK11195. The 50% inhibitory concentration was determined and the dissociation constant (Ki) value was derived by the equations derived so far (Cheng Y. et al. Biochem Pharmacol. 1973; 22: 3099-3108). The protein concentration was estimated by the method of Lowry et al. (J Biol Chem. 1951; 193: 265-275) using bovine serum albumin (Sigma-Aldrich) as a standard substance.

6). Radiolabel using [ ¹⁸ F]

Scheme 10: Radiolabeling with ¹⁸ F.
As will be appreciated by those skilled in the art, the compound of formula (III) or (IV) may be radiolabeled at any position on the compound. For example, a compound of formula (III) or (IV) may be radiolabeled with a phenyl substituent via an ethoxy group using a tosyl or fluoro precursor, or using a tosyl or fluoro precursor The acetamide functional group may be labeled directly by

Radiosynthesis of [ ¹⁸ F] PDAZ-FE (20) Radioisotope production. Irradiation of water target with 0.8 mL silver body using 25 μA current and 16.5 MeV proton beam to 95% enriched [ ¹⁸ O] H ₂ O by [ ¹⁸ O (p, n) ¹⁸ F] nuclear reaction Produced an aqueous [ ¹⁸ F] fluoride ion with no support added with a PETtrace cyclotron (GE Healthcare, Sweden).

Preparation of ^{K [18 F] F-Kryptofix} 2.2.2. ^[18 O] in _{H 2} O ^[18 F] fluoride was transferred to GE TRACERlab FX _F-N synthesizer, washed with anion exchange resin (10mL 0.5M K ₂ CO _3, then is water 10mL Passed through a Sep-Pak Waters Accel ™ Light QMA cartridge in carbonate form, prepared by drying with N ₂ under vacuum, then the eluent [K ₂ CO ₃ (4 mg), Kryptofix 222 (13 mg), containing 100 μL of sterile water and acetonitrile (900 μL)], the captured [ ¹⁸ F] fluoride was eluted from the Sep-Pak cartridge, transferred to a reaction vessel, and then helium flow and vacuum Evaporation by heating under 70 ° C. Subsequently, the reaction vessel Acetonitrile (1 mL) was added to and evaporated to dryness by heating at 120 ° C. under vacuum.

Preparation and formulation of [ ¹⁸ F] PDAZ-FE. Tosyl precursor (8,2mg), was dissolved in acetonitrile (1 mL), was added anhydrous ^K [18 F] F-Kryptofix2.2.2 complex. The mixture was reacted at 100 ° C. for 10 minutes. Upon completion, the reaction mixture was diluted with sterile water (1 mL) and transferred to a separate container. The reaction vessel was rinsed with sterile water (0.5 mL) and transferred to the same vessel. The entire crude mixture (contained in the vessel) is then placed in an HPLC Waters XTerra RP C-18 (10 μm, 7.8 × 300 mm) semi-reverse phase column (contained in the same hot cell as the TRACERlab FX _F-N module). Provided. The mobile phase of 0.1 M NH ₄ Ac (pH 10): CH ₃ CN; (65:35, v: v), with a flow rate of 4.0 mL / min, the t _R of [ ¹⁸ F] PDAZ-FE is 25 minutes there were. Radioactive fractions corresponding to [ ¹⁸ F] PDAZ-FE were collected in round bottom flasks containing sterile water (40 mL). Subsequently, the entire solution was passed through a tC-18 Sep-Pak cartridge. The tC18 captured and radiolabeled product was further rinsed with sterile water (5 mL). The product is then eluted from the tC18 Sep-Pak cartridge with EtOH (0.5 mL) and sterile water (5 mL), then filtered through a sterile 13 mm Millipore GS 0.22 μm filter and 10 mL sterile pyrogen free. Placed in a vial.

[ ¹⁸ F] PDAZ-FE quality control. For determination of specific activity and radiochemical purity, an aliquot of the final solution of known volume and activity was analyzed with an analytical reverse phase HPLC column Phenomenex Luna RP C-18 column (5 μm, 4.6 × 250 mm), Subjected to a mobile phase of H ₂ O: TFA: ACN (65: 0.01: 35, v: v) at a flow rate of 1 mL / min. Using these conditions, [ ¹⁸ F] PDAZ-FE had a retention time (t _R ) of 6.2 minutes. The area of the UV absorbance peak measured at 254 nm, corresponding to the carrier product, was measured (integrated) on the HPLC chromatogram and compared to a standard curve relating mass to UV absorbance. The tosylate precursor (Compound 8) exhibited a t _R of 31.6 min.

[ ¹⁸ F] PDAZ-FE normal rat microPET study All PET data was acquired using a MicroPET Focus 220 animal scanner. First, rats were anesthetized using isoflurane (Troy Laboratories Pty Ltd, Australia) gas (5% for introduction and 1-4% for maintenance). The rat head was fixed using a perspex stereotactic frame to minimize motion artifacts. A ⁵⁷ Co rod source was used for the head (8 min) transmission scan just prior to the release study for absorption correction purposes. Acquisition of PET data in wrist mode was started immediately before administration of 60 MBq [ ¹⁸ F] PDAZ-FE in 100 μL of sterile water and continued for 60 minutes. At the end of each study, the list mode data was sorted into dynamic sinograms containing 24 frames (10 × 30 s, 5 × 120 s and 9 × 300 s). The dynamic 3-D PET sinogram was reconstructed into 95 cross-sectional sections each containing 128 × 128 voxels using 3D reprojection (zoom 4.745). The reconstructed voxel value in each frame was in units of Bq / mL, corrected for radioactive decay against injection time, and the voxel dimensions were 0.400 × 0.400 × 0.796 cm. The voxel values were then converted to units of standard intake values (SUV) and then to the injected dose% / mL. A TAC versus time representing the variation in ligand concentration was constructed for the entire brain. After acquiring the list mode, a whole body PET scan was performed at 4 different bed positions for 5 minutes to determine total body activity. Absorption correction, scattering correction, and dead time correction were applied to all data.

The second study involved pretreating rats with PK11195 (3 mg / kg) for 5 minutes prior to [ ¹⁸ F] PDAZ-FE (26 MBq in 100 μL sterile water). Both PK11195 and radioligand were administered by rat tail vein. Figure 1 ^illustrates a [18 F] PDAZ-FE of rats administered, and PK11195 are pretreated with ^[18 F] PDAZ-FE MircoPET image taken of rats administered.

  Although the invention has been described with reference to specific embodiments, those skilled in the art will appreciate that the invention may be embodied in many other forms.

Claims (62)

Formula (III)

[Where:
R ¹² and R ¹³ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ¹² and R ¹³ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 7 ring members that may be substituted;
R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl , COOR ²² , (CH ₂ ) _n OR ²² or an optionally substituted polyether;
R ¹⁹ and R ²¹ are each independently halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, Aryl which may be substituted, heteroaryl which may be substituted, NHC _1-6 alkyl which may be substituted, SC _1-6 alkyl which may be substituted, COOR ²² , (CH ₂ ) _n OR ²² or an optionally substituted polyether;
R ²⁰ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ²² , (CH ₂ ) _n OR ²² or substituted Which may be a polyether;
R ²² is an optionally substituted alkyl;
n is an integer from 1 to 6]
Or a salt or solvate thereof. The compound of claim 1, wherein R ²⁰ is H. The compound according to claim 1 or 2, wherein R ¹⁹ and R ²¹ are each independently C _1-6 alkyl. The compound according to any one of claims 1 to 3, wherein R ¹⁹ and R ²¹ are each independently methyl. R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H, halo, OH, NO ₂ , optionally substituted C _1-6 alkyl, optionally substituted OC ₁ The compound according to any one of claims 1 to 4, which is _-6 alkyl or optionally substituted aryl. The compound according to any one of claims 1 to 5, wherein R ¹⁴ , R ¹⁵ , R ¹⁷ and R ¹⁸ are H. The R ^{16 according} to any one of claims 1 to 6, wherein R ¹⁶ is halo, OH, optionally substituted C _1-6 alkyl, or optionally substituted OC _1-6 alkyl. Compound. The compound according to any one of claims 1 to 7, wherein R ¹² and R ¹³ are each independently C _1-6 alkyl. The compound according to any one of claims 1 to 8, wherein R ¹² and R ¹³ are each independently ethyl. The compound or salt or solvate thereof according to any one of claims 1 to 9, which is selected from the group consisting of:

and

Formula (IV)

[Where:
R ²³ and R ²⁴ are each independently selected from the group consisting of H, benzyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, aryl and heteroaryl, each of which is Optionally substituted with _one or more halo or C ₁ -C ₆ alkyl;
Or R ²³ and R ²⁴ together with the nitrogen to which they are attached form an optionally substituted heterocycle having 3 to 7 ring members;
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or an optionally substituted polyether;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is selected from the group consisting of O, NH and S;
I, J, K and L are each independently CR ³¹ or N;
R ³¹ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted Which may be a polyether;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, Optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl]
Or a salt or solvate thereof.   The compound according to claim 11, wherein X is O. Wherein I is N, said J, K, L is ^{CR 31,} A compound according to claim 11 or claim 12. The I, J, K and L is a ^{CR 31,} claim 11 or compound of claim 12. Wherein each R ³¹ is, independently, H, optionally halo or an optionally substituted alkyl, A compound according to any one of claims 11 to 14. The compound according to any one of claims 11 to 15, wherein R ²⁵ , R ²⁶ , R ²⁸ and R ²⁹ are H. The compound according to any one of claims 11 to 16, wherein R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are H. 18. The method according to claim 11, wherein R ²⁷ is halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted aryl. Compound described in 1. Wherein ^{R 27} _is, OH, _CH 3, OCH _3, a NO 2, F, Cl or naphthyl, A compound according to any one of claims 11 to 18. Wherein ^{R 27} is, F, Cl or OCH _3, A compound according to any one of claims 11 to 19. Wherein ^{R 23} and ^{R 24} are each _{independently C 1-6} alkyl, A compound according to any one of claims 11 to 20. Wherein R ²³ and R ²⁴ are each independently ethyl, it is selected from the group consisting of propyl and i- propyl, compound according to any one of claims 11 to 21.

and

The compound or a salt or solvate thereof according to any one of claims 11 to 22, which is selected from the group consisting of:   24. A compound according to any one of claims 11 to 23, wherein the compound is the (R) -enantiomer. Formula (V) for use as an intermediate in the preparation of compounds of formula (IV)

[Where:
R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and R ²⁹ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted. Good alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 Alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or an optionally substituted polyether;
R ³⁰ is an optionally substituted alkyl;
n is an integer from 1 to 6;
X is selected from the group consisting of O, NH and S;
I, J, K and L are each independently CR ³¹ or N;
R ³¹ is H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Good aryl, optionally substituted heteroaryl, optionally substituted NHC _1-6 alkyl, optionally substituted SC _1-6 alkyl, COOR ³⁰ , (CH ₂ ) _n OR ³⁰ or substituted Which may be a polyether;
R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are each independently H, halo, OH, NO ₂ , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, Optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl]
Or a salt or solvate thereof wherein R ²⁷ is not methyl when I is N.   26. The compound of claim 25, wherein X is O.

and

27. The compound according to claim 25 or claim 26, or a salt or solvate thereof, selected from the group consisting of:   The compound according to any one of claims 1 to 24, which is radiolabeled with a radioisotope. The radioisotope ^{is, 18 F, 123 I, 76} Br, 124 is selected from I and ⁷⁵ Br, compound of claim 28. The radioisotope is ^{18 F,} the compound according to claim 29.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 24 or claim 28 to claim 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.   32. A method of diagnosing a disorder in a subject comprising administering to the subject a compound according to any one of claims 1 to 24 or 28 to 30.   35. The method of claim 32, comprising imaging translocator protein (18 kDa) (TSPO) in a subject.   34. The method of claim 33, comprising obtaining an image showing the location of the protein. 35. Any of claims 32 to 34, wherein the compound is radiolabeled with a radioisotope, and the radioisotope is selected from the group consisting of ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br. 2. The method according to item 1. 36. The method of claim 35, wherein the compound is radiolabeled with ¹⁸ F, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br and the image is obtained by positron emission tomography (PET) imaging. 36. The method of claim 35, wherein the compound is radiolabeled with ¹²³ I and the image is obtained by SPECT imaging.   38. The method of any one of claims 34 to 37, wherein the image is obtained to assess the extent of TSPO binding of the compound or salt thereof in the subject's brain parenchyma.   35. The method of claim 32, wherein the disorder is a neurodegenerative disorder, inflammation or anxiety.   The disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumor, anxiety, stress, emotional disorder or cognitive impairment, glioblastoma, imaginary 33. The method of claim 32, selected from the group consisting of bloody stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, cortical basal ganglia, cancer, depression, autoimmune disease and infectious disease.   41. The method of any one of claims 32 to 40, wherein the subject is a human.   32. Use of a compound according to any one of claims 1 to 24 or 28 to 30 in the manufacture of a medicament for diagnosing a disorder in a subject.   43. Use according to claim 42, wherein diagnosing the disorder comprises imaging a translocator protein (18 kDa) in the subject. 44. The compound of claim 42 or 43, wherein the compound is radiolabeled with a radioisotope, and the radioisotope is selected from the group consisting of ¹⁸ F, ¹²³ I, ⁷⁶ Br, ¹²⁴ I and ⁷⁵ Br. Uses. 45. Use according to claim 44, wherein the compound is radiolabeled with ¹⁸ F, ⁷⁶ Br, ¹²⁴ I or ⁷⁵ Br and the translocator protein image is obtained by positron emission tomography (PET) imaging. 45. Use according to claim 44, wherein the compound is radiolabeled with ¹²³ I and a translocator protein image is obtained by SPECT imaging.   43. Use according to claim 42, wherein the disorder is a neurodegenerative disorder, inflammation or anxiety.   The disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumor, anxiety, stress, emotional disorder or cognitive impairment, glioblastoma, imaginary 43. Use according to claim 42, selected from the group consisting of bloody stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, autoimmune disease and infectious disease. Reacting a compound of formula (VII) with a compound of formula (VIII),

Wherein R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ are defined by any one of claims 1 to 9 and Y Is a leaving group that reacts with VII]
A process for preparing a compound of formula (III), or a salt or solvate thereof.   50. The method of claim 49, wherein Y is halo.   51. A compound of formula (III) when prepared by the method of claim 49 or claim 50. Reacting a compound of formula (V) with a compound of formula (VI),

Wherein I, J, K, L, X, R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ , R ²⁹ , R ³³ , R ³⁴ , R ³⁵ and R ³⁶ are claimed Defined by any one of claims 11 to 22]
A process for preparing a compound of formula (IV), or a salt or solvate thereof.   53. A compound of formula (IV) produced by the method of claim 52.   31. A compound according to any one of claims 1 to 24 or 28 to 30 capable of eliciting a response when bound to a TSPO receptor.   32. Use of a compound according to any one of claims 1 to 24 or 28 to 30 in the manufacture of a medicament for the treatment of the disorder in a subject.   56. Use according to claim 55, wherein the disorder is characterized by an abnormal density of TSPO receptors in mammals.   56. Use according to claim 55, wherein the disorder is a neurodegenerative disorder, inflammation or anxiety.   The disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumor, anxiety, stress, emotional disorder or cognitive impairment, glioblastoma, imaginary 56. Use according to claim 55, selected from the group consisting of bloody stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, autoimmune disease and infectious disease.   32. A method of treating a disorder in a subject, comprising administering to the subject a compound of any one of claims 1 to 24 or 28 to 30.   60. The method of claim 59, wherein the disorder is characterized by an abnormal density of TSPO receptors in a mammal.   60. The method of claim 59, wherein the disorder is a neurodegenerative disorder, inflammation or anxiety in a subject.   The disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, multiple system atrophy, epilepsy, encephalopathy, stroke, brain tumor, anxiety, stress, emotional disorder or cognitive impairment, glioblastoma, imaginary 60. The method of claim 59, selected from the group consisting of bloody stroke, herpes encephalitis, HIV, amyotrophic lateral sclerosis, corticobasal degeneration, cancer, depression, autoimmune disease and infectious disease.

Images